Vascular resistance changes induced by hydralazine and other antihypertensive drugs and hormones may be dependent upon prostaglandin (PG) synthesis. Vasodilation mediated by PGs is strongly suggested by increased PG levels in venous blood from the kidney or other organs and antagonism of vasodilator effects by PG cyclo-oxygenase inhibition. In previous studies, however, responses to PG synthesis inhibition and venous PG levels were studied in anesthetized animals subjected to acute surgical stress, a state in which the renin-angiotensin system is known to be stimulated. "Turning on" of PG synthesis by angiotensin II may have greatly altered the responses. The proposed research is aimed at determining the effects of hydralazine on PG levels in venous blood from the kidney and other regional vascular beds in conscious, chronically-instrumented preparations. PG efflux will be determined in conjunctions with measurements of vascular resistance and renin secretion. Alteration in the pattern of renal PG metabolism and renin release induced by changes in dietary sodium chloride intake will be examined to identify functional consequences in terms of renal handling of water and electrolytes. the above experiments will help to clarify the intricate relationship between renal PGs and control of renin secretion. Simultaneous changes in the profile of renal PG synthesis and renin release evoked by hydralazine and other antihypertensive drugs will also be studied in anesthetized animals subjected to minimal surgical stress, isolated perfused kidneys, and in non-filtering kidneys. In parallel to these in vivo experiments, enzymic pathways of arachidonate metabolism which regulate renin secretion will be investigated and the hypothesis that 6-keto-PGE1 may participate in this control tested. Activity of PGE2-9-ketoreductase will be assayed in isolated kidneys through transformation of tritiated PGE2 to radiolabeled PGF2Alpha. This activity as well as that of hydroxyprostaglandin dehydrogenases will also be studied in high speed supernates prepared from homogenized kidney and vascular tissues of treated animals. Thus, the proposed research will examine PG-mediated effects using systems of varied complexity, ranging from intact animals to subcellular fractions. Research directed at fundamental mechanisms underlying vascular and renin responses to antihypertensive agents, such as hydralazine, may well have direct application to drug therapy of hypertension.